1. Field of the Invention
The invention relates to conjugates of hydrophilic biopolymers such as hyaluronans (including hylans) with drugs or other pharmacologically active substances including anti-neoplastic drugs such as alpha-interferon formed by covalently bonding them with divinyl sulfone (“DVS”); sometimes referred to herein as vinylsulfone, methods of preparing them and using them.
2. Description of Related Art
Conjugation of polyethylene glycol (“PEG”) and certain biological polymers and enzymes including insulin and catalase are disclosed in U.S. Pat. No. 4,179,337. U.S. Pat. Nos. 5,539,063 and 6,042,822 disclose respectively, (a) methods of conjugation of PEG using so-called “unique linkers” to improve the attachment and activity of the conjugates; and (b) active conjugates of alpha-interferon to PEG. U.S. Pat. No. 5,366,958 discloses the attachment of biologically active agents to fibronectin using N-hydroxysuccinimide; and International Patent No. WO 0,078,365 teaches oxidizing hyaluronans to form aldehyde groups reactive with diamines or amino polyalkylene glycols which are then reacted with oxidized sulfated polysaceharides. In U.S. Pat. Nos. 4,582,865 and 4,605,681, the preparation of cross-linked hyaluronan though vinyl sulfone linkages, as well as the attachment of these materials to the matrix of an insoluble gel-via ether linkages are described.
Prestwich, Glenn D., in “Biomaterials from Chemic ally-Modified Hyaluronan, Glycoforum (Mar. 29, 2001) suggests that drags way be conjugated with hyaluronan. Finally, Cirino, et al., Carbohydrate Research (1971), 17(1), 67–68) teaches that, in addition to simple cross-links (a) and simple substitutions (b), divinyl sulfone can also react with carbohydrates (e.g., cellulose, D-glucose) leading to complex modification of the carbohydrate: RO—CH2—CH2—SO2—CH2—CH2—OR; and (b) RO—CH2—CH2—SO2—CH═CH2, wherein R is a carbohydrate.